Angiogenesis is the generation of new blood vessels from parent microvessels. Controlled and uncontrolled angiogenesis proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a “sprout” off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel.
Angiogenesis, Modulators and Associated Diseases
Angiogenesis is highly regulated by a system of angiogenic stimulators and inhibitors. Known examples of angiogenesis stimulators include certain growth factors, cytokines, proteins, peptides, carbohydrates and lipids (Norrby, APMIS, 105:417-437 (1997); Polverini, Crit. Rev. Oral. Biol. Med., 6:230-247 (1995)). A variety of endogenous and exogenous angiogenesis inhibitors are known in the art (Jackson et al., FASEB, 11:457-465 (1997); Norrby, APMIS, 105:417-437 (1997); and O'Reilly, Investigational New Drugs, 15:5-13 (1997)).
In adult organisms, capillary endothelial cells divide relatively infrequently. When triggered by appropriate signals, e.g., in response to hormonal signals during menses or following the release of pro-angiogenic mediators sequestered in the extracellular matrix, endothelial cells lining venules will systematically degrade their basement membrane and proximal extracellular matrix, migrate directionally, divide, and organize into new functioning capillaries, within a matter of days (Polverini, Crit. Rev. Oral. Biol. Med., 6:230-247 (1995)). This dramatic amplification of the microvasculature is nevertheless temporary, for as rapidly as the new capillaries are formed, they virtually disappear within a matter of days or weeks, returning the tissue microvasculature to its status quo. It is this feature of transient growth and regression of capillaries that primarily distinguishes physiological angiogenesis from a pathological one (Polverini, Crit. Rev. Oral. Biol. Med., 6:230-247 (1995)). In contrast, pathological angiogenesis is caused by a shift in the net balance between stimulators and inhibitors of angiogenesis, e.g., due to the overproduction of normal or aberrant forms of angiogenic mediators, or due to a relative deficiency in inhibitors of this process (Polverini, Crit. Rev. Oral. Biol. Med., 6:230-247 (1995)).
Angiogenesis is essential for normal placental, embryonic, fetal and post-natal development and growth, but almost never occurs physiologically in adulthood except in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta. Angiogenesis in the adult is often associated with disease states.
Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, tumor metastasis and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions. The diverse pathological disease states in which unregulated angiogenesis is present have been grouped together as angiogenic dependent or angiogenic associated diseases.
The control of angiogenesis is altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to uncontrolled angiogenesis (see generally Norrby, APMIS, 105:417-437 (1997); and O'Reilly, Investigational New Drugs, 15:5-13 (1997)). Thus, angiogenesis is involved in the manifestation or progress of various diseases, for example, various inflammatory diseases, such as rheumatoid arthritis, psoriasis, diabetic retinopathies, certain ocular disorders, including recurrence of pterygii, scarring excimer laser surgery and glaucoma filtering surgery, various disorders of the anterior eye, cardiovascular disorders, chronic inflammatory diseases, wound repair, circulatory disorders, crest syndromes, dermatological disorders (see, e.g., U.S. Pat. Nos. 5,593,990, 5,629,327 and 5,712,291) and notably cancer, including solid neoplasms and vascular tumors. Several lines of direct evidence indicate that angiogenesis is essential for the growth and persistence of solid tumors and their metastases.
Thus, it is clear that angiogenesis plays a major role in the metastasis of cancer and in the pathology of a variety of other disorders. Repressing, eliminating or modulating this activity, should impact the etiology of these diseases and serve as a point of therapeutic intervention. In the disease state, prevention of angiogenesis could avert the damage caused by the invasion of the new microvascular system. Therapies directed at control of the angiogenic processes could lead to the abrogation or mitigation of these diseases.
Hence there is a need to develop therapeutics that target angiogenesis and modulate, particularly, inhibit aberrant or uncontrolled angiogenesis. Therefore it is an object herein to provide assays for identification of such agents. It is also an object herein to provide nucleic acids encoding the proteins and polypeptides and also to provide the proteins and polypeptides that are involved in the regulation of angiogenesis.